Theophylline Improves Hypoglycemia Unawareness in Type 1 Diabetes

Abstract

Iatrogenic hypoglycemias and the subsequent occurrence of hypoglycemia unawareness are well-known complications of intensive insulin therapy in type 1 diabetic patients that limit glycemic management. From a pharmacological point of view, the adenosine-receptor antagonist theophylline might be beneficial in the management of hypoglycemia unawareness. Theophylline stimulates the release of catecholamines and reduces cerebral blood flow, thereby facilitating stronger metabolic responses to and a prompter perception of decreasing glucose levels. To test the effect of theophylline on responses to hypoglycemia, we performed paired hyperinsulinemic-hypoglycemic clamp studies in 15 diabetic patients with hypoglycemia unawareness and 15 matched healthy control subjects. In random order, we concurrently infused either theophylline or placebo. Measurements included counterregulatory hormones, symptoms, hemodynamic parameters, and sweat detection using a dew-point electrode. Additionally, middle cerebral artery velocities (V MCA ) using transcranial Doppler were monitored as an estimate of cerebral blood flow. When compared with placebo, theophylline significantly enhanced responses of plasma epinephrine, norepinephrine, and cortisol levels in both diabetic patients and control subjects. Because of the theophylline, sweat production started at ϳ0.3 mmol/l higher glucose levels in both groups (P < 0.01), and symptom scores in diabetic patients approached those in control subjects. Theophylline decreased V MCA in both groups (P < 0.001), but significantly greater in diabetic patients (P < 0.01), and prevented the hypoglycemia-induced increase of V MCA that occurred during the placebo studies. We conclude that theophylline improves counterregulatory responses to and perception of hypoglycemia in diabetic patients with impaired awareness of hypoglycemia. Diabetes 51:790 -796, 2002

Minimizing Hypoglycemia While Maintaining Glycemic Control in Diabetes

“…Patients were recruited to a study in which theophylline was given as an intravenous infusion during a slow-fall hypoglycemic clamp (42). The rise in cerebral blood flow was prevented, and the threshold for the increase in symptoms and epinephrine shifted to a higher level, although there was no increase in glucagon concentrations.…”

The Contribution of Medications to Hypoglycemia Unawareness

“…Both have been shown to magnify the counterregulatory hormone (i.e., epinephrine, norepinephrine, and cortisol) response to hypoglycemia, as well as recovery from and perception of hypoglycemia in patients with type 1 diabetes both with and without hypoglycemia unawareness. 1 One study 18 evaluating the impact of theophylline on the response to hypoglycemia compared 15 patients with type 1 diabetes who had a history of hypoglycemia unawareness to 15 matched healthy control subjects. The subjects underwent hyperinsulinemichypoglycemic glucose clamp and randomly received either theophylline or placebo in a crossover fashion.…”

The involvement of upstream stimulatory factor 1 in Dutch patients with familial combined hyperlipidemia

“…Glucose concentrations were analyzed in duplicate using the oxidation technique (BeckmanT Glucose Analyser2; Beckman Instruments, Inc.). Plasma insulin concentrations were ascertained using a double antibody method (36). Insulin resistance was assessed by the homeostasis model assessment (HOMA) method (37).…”